tbuckley/cabot-search huggingface dataset:
Abstract 3688: Exploring metabolic vulnerabilities of metastatic prostate cancer to bone
Authors: Federica Mossa, Daniele Robesti, Christopher Vellano, Mark Titus, Joe Marszalek, Daniel Frigo, Christopher Logothetis, Taranjit Gujral, Eleonora Dondossola
Journal: Cancer Research (2023)

Abstract Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. Here, we investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of oxidative phosphorylation in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. Metabolic in vitro analyses showed that C4-2B cells depended on aerobic respiration, while PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-010759, a clinical grade inhibitor of oxidative phosphorylation tested in patients. In vivo studies confirmed a significant reduction by IACS-010759 in C4-2B tumors implanted subcutaneously or in bone, and no effect in subcutaneous PC3 tumors. Unexpectedly, PC3 tumors in bone responded to IACS-010759, indicating a microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies with aerobic respiration being a major driver of ARPC, while AVPC depends on glycolysis, but can undergo metabolic reprogramming in bone. Such metabolic vulnerabilities may be exploited to either introduce further lines of treatments or in combination with the existing therapies. These findings also underscore the important role that the tumor microenvironment can play in reprogramming prostate cancer metabolism and thus, influence the efficacy of metabolically targeted therapies. Citation Format: Federica Mossa, Daniele Robesti, Christopher Vellano, Mark Titus, Joe Marszalek, Daniel Frigo, Christopher Logothetis, Taranjit Gujral, Eleonora Dondossola. Exploring metabolic vulnerabilities of metastatic prostate cancer to bone. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3688.
Abstract 3717: Defining the mechanism of ER receptor transcription complex activity and its effect on epigenetic modulations using super resolution microscopy
Authors: Tara Akhshi, Myles Brown
Journal: Cancer Research (2023)

Abstract Estrogen Receptor α (ERα) is expressed in ER+ breast cancers, one of the leading causes of death among women. Despite effectiveness of endocrine therapy, a significant number of patients experience resistance to these treatments. One of the major hurdles is lack of comprehensive information about ERα transcriptional complex activity. While biochemical assays have improved our knowledge significantly, it is critical to imply techniques that allow direct visualization of ERα activity and gain spatiotemporal information. We used super resolution microscopy to examine the mechanism of ERα transcriptional activity. We showed that ERα interactions with its co-activators (P300, SRC-3), is influenced upon administration of Tamoxifen and Fulvestrant, an effect that is lost in cells carrying multination in ERα ligand binding site. Additionally mutant cells are no longer able to recruit ERα co-inhibitor (NCORI). Using STORM microscopy, we showed estrogen treatment caused an “open” chromatin (H3K27ac) structure which may represent active areas of gene expression, while Tamoxifen and Fulvestrant treatments caused chromatin to form “closed” structures which likely represent close and inactive phase of chromatin. Citation Format: Tara Akhshi, Myles Brown. Defining the mechanism of ER receptor transcription complex activity and its effect on epigenetic modulations using super resolution microscopy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3717.
Abstract 3716: RNA N6-methyladenosine binding protein, YTHDF1 regulates DNA repair and cancer immunity in protein synthesis levels
Authors: Dongjun Jang, Hae Rim Jung, Jaeik Oh, Sung-Yup Cho
Journal: Cancer Research (2023)

Abstract N6-methyladenosine RNA methylation is one of the most abundant post transcriptional modifications in eukaryotic messenger RNAs and plays crucial roles in cancer development and progression. YTHDF1 is an m6A reader protein and has been reported to increase the translation of mRNAs in cooperation with YTHDF3. In gastric cancer, YTHDF1 was reported to be overexpressed in cancer tissues, but detailed effects of YTHDF1 in cancer immunity have not been fully elucidated. In RNA sequencing data from a TGCA gastric cancer cohort, the expression of YTHDF1 was inversely correlated with the cytotoxic T cell markers, such as CD8A, GZMA, and GZMB. To investigate the effect of YTHDF1 overexpression on gene expression regulation in protein levels, we performed the proteomic analysis for newly synthesized proteins using non-canonical amino acid azidohomoalanine and click chemistry tagging reaction in the presence of interferon-γ (IFN-γ). Protein synthesis of genes in ‘DNA damage response’ and ‘DNA repair’ gene sets increased in YTHDF1-overexpressed samples. On the contrary, protein synthesis of genes in ‘Allograph rejection’, ‘NK cell mediated cytotoxicity’, and ‘NF-κB signaling’ gene sets decreased in YTHDF1-overexpressed samples. Especially, YTHDF1 reduced basal expression of DNA damage marker, γH2AX, suggesting that DNA damage repair was enhanced by YTHDF1 overexpression. Our study suggests that YTHDF1 plays pervasive roles in DNA repair and cancer immunity by regulating gene expression in protein levels. Citation Format: Dongjun Jang, Hae Rim Jung, Jaeik Oh, Sung-Yup Cho. RNA N6-methyladenosine binding protein, YTHDF1 regulates DNA repair and cancer immunity in protein synthesis levels. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3716.
Abstract 3703: Multimodal metabolic imaging and proteomics of radiation resistance in head and neck squamous cell carcinoma
Authors: Jesse D. Ivers, Sina Dadgar, Narasimhan Rajaram
Journal: Cancer Research (2023)

Abstract Radiation resistance can halt a well-curated treatment plan in its tracks, but it may take weeks to realize this lack of efficacy resulting in lost time and unnecessary side effects. In this study, we sought to elucidate novel biomarkers of radiation resistance to predict treatment response in head and neck squamous cell carcinoma (HNSCC) at much earlier timepoints. We grew tumor xenografts from radiation-resistant UM-SCC-47 (n=25) and -sensitive UM-SCC-22B (n=37) cells in nude athymic mice. Each group was randomly divided into treatment and control groups, which were further subdivided into four timepoints for tumor excision: pre-treatment baseline, 1-, 24-, and 48-hours post-treatment. Prior to excision, we injected pimonidazole to quantify tumor hypoxia. We determined the two-photon excited fluorescence intensity and lifetime of NADH and FAD and quantified the optical redox ratio, ratio of free to bound NADH, and mean NADH lifetime of frozen sections of each tumor. We observed spatial and temporal heterogeneity in these high-resolution optical maps that indicated different metabolic programs in radiation-resistant and -sensitive tumors. A histogram-based heterogeneity analysis revealed time dependent shifts toward glycolysis in the radiation-resistant UM-SCC-47 treatment group, while the sensitive UM-SCC-22B treatment group showed the opposite trend. Proteomics performed on both cell lines identified multiple dysregulated proteins that are often implicated in HNSCC and associated with metabolic reprogramming — specifically, EGFR and SMAD4. We also found elevated levels of hypoxia and HIF-1 in the UM-SCC-47 tumors compared with the UM-SCC-22B tumors prior to and post-radiation. Using spatially co-registered optical imaging and immunohistochemical maps of the same field of view, we will present correlations between our optical markers and EGFR, SMAD4, and HIF-1. These studies will provide evidence of how protein dysregulation causes changes to optical metabolic imaging markers. Citation Format: Jesse D. Ivers, Sina Dadgar, Narasimhan Rajaram. Multimodal metabolic imaging and proteomics of radiation resistance in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3703.
Abstract 2281: Dual immune checkpoint blockade induces analogous alterations in the dysfunctional CD8+ T cell and activated Treg compartment
Authors: Anne M. van der Leun, Joleen J. Traets, Joris L. Vos, Joris B. Elbers, Sanne Patiwael, Xiaohang Qiao, Mercedes Machuca-Ostos, Daniela S. Thommen, John B. Haanen, Ton N. Schumacher, Charlotte L. Zuur
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade has shown clinical activity in a range of cancer types. To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in head and neck squamous cell carcinoma, we analyzed immune infiltrates in tumor biopsies from responding and non-responding patients. At baseline, a higher ratio between active (4-1BB+) and inactive regulatory CD4+ T cells was associated with response to therapy. Furthermore, upon therapy, this active Treg population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells transitioned to a state of reduced activity and dysfunction in responding patients, while in non-responding patients, NK cells showed an increased cytotoxic transcriptional profile upon treatment. These data reveal the immunological changes in response to dual PD-1 and CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive T cell compartments in responding patients, and indicate that the presence of an activated Treg compartment at baseline may predict response. Citation Format: Anne M. van der Leun, Joleen J. Traets, Joris L. Vos, Joris B. Elbers, Sanne Patiwael, Xiaohang Qiao, Mercedes Machuca-Ostos, Daniela S. Thommen, John B. Haanen, Ton N. Schumacher, Charlotte L. Zuur. Dual immune checkpoint blockade induces analogous alterations in the dysfunctional CD8+ T cell and activated Treg compartment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2281.
Abstract 3704: The essential role of an alternate mRNA translation initiation in the regulation of breast cancer cell metabolism
Authors: Hanna Rosenstock, Erna Mitaishvili, Columba de la Parra
Journal: Cancer Research (2023)

Abstract Translational control and metabolic reprogramming are hallmarks of advanced cancers. Important genes involved in cancer progression express mRNAs that are selectively translated, including regulators of cancer cell metabolism. Cancer cells acquire an altered metabolism, switching from oxidative phosphorylation (OXPHOS) to a glycolytic phenotype (Warburg effect), to increase reliance on alternate metabolic pathways to support growth, proliferation, and metastasis. Triple-negative breast cancer (TNBC), one of the most aggressive and highly metastatic subtypes with the poorest outcome, is characterized by elevated glycolysis and low OXPHOS. Still, the exact mechanism for this metabolic switch is largely unknown. Using a TNBC cell model it has been shown an alternate mechanism of cap-dependent but mTORC1/eIF4Eindependent mRNA translation by the eIF4G homolog, DAP5, which directly binds the cap-binding protein eIF3d. Our research indicates that this alternate translation initiation is essential in regulating several mRNAs involved in breast cancer metabolism. DAVID analysis from genome-wide transcriptomic and translatomic studies, metabolomic assays including Glycolysis Assay [Extracellular Acidification], Oxidative Phosphorylation, and Mitotracker Assay, as well as RT-PCR and western blot analysis was performed from well-characterized triple-negative aggressive breast cancer cell lines,4T1 and MDA-231, Non-silencing (Nsi) control and silencing DAP5 (shDAP5) samples. Several mRNAs related to glucose metabolism decreased after silencing DAP5 and on the opposite, critical mRNAs associated with OXPHOS increased, independent of their steady-state mRNA abundance. Silencing DAP5 increased Oxidative Phosphorylation activity and decrease the glycolytic rate in TNBC breast cancer cells. Proteins correlated with aberrant glycolytic metabolism including the E-cadherin transcriptional repressors Snail (SNAI1) were reduced after silencing of DAP5. Our data indicates that the alternate mRNA translation initiation mechanism by DAP5 of specific mRNAs correlated to glycolysis and OXPHOS could play an essential role in the mechanism by which TNBC breast cancer cells orchestrate a metabolic switch required for malignant progression and metastasis. Citation Format: Hanna Rosenstock, Erna Mitaishvili, Columba de la Parra. The essential role of an alternate mRNA translation initiation in the regulation of breast cancer cell metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3704.
Abstract 1425: TTFields reduce sensitivity in glioblastoma is associated with the functional expression of the chloride intracellular channel 1 and with voltage dependent sodium channel
Authors: Stefania Castiglione, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Chiara Biella, Chiara Mercurio, Emanuela Pastorelli, Monica Lupi, Laura Paracchini, Laura Mannarino, Dietmar Krex, Federico Brandalise, Michele Mazzanti
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most aggressive type of brain tumor, and existing treatments are inadequate at preventing recurrence. Tumor Treating Fields (TTFields) is a novel treatment that has been proven to extend patients' lives during the previous two decades. The antitumoral impact of TTFields involve different mechanism and is an optional add-on to standard temozolomide maintenance. Although TTFields therapy slows tumor progression initially, it does not prevent tumor relapse in most patients. We subjected patient-derived GBM primary cultures to continuous TTFields stimulation to mimic the GBM standard of care and examine the molecular pathways behind GBM sensitivity to TTFields treatment. TTFields initially limit cellular growth well. However, even under constant TTFields administration, the remaining cells regain their ability to proliferate at their own rate in long-term trials. Prolonged treatment with TTFields increases the expression of many stemness markers as well as the overexpression of different genes involved in cell cycle progression. There is also a rise in membrane ionic conductance activity. After sustained exposure to TTFields, sodium, potassium, and chloride channels are functionally increased. This influences the properties of tumor cells. Increased sodium channel functional activity, for example, promotes membrane potential depolarization. Furthermore, earlier research has shown that the membrane form of the chloride intracellular channel 1 (tmCLIC1) is important in the development of GBM. In patient-derived GBM cells exposed to TTFields, tmCLIC1 is significantly concentrated, and membrane depolarization improves its function. The evaluation of GBM tissues obtained from many patients who were treated with TTFields validates the in vitro tumor relapse model.Our findings imply that the process by which GBM cells develop a decrease in sensitivity to TTFields correlates with an increase in stemness markers and an increase in ionic channel functional expression. Citation Format: Stefania Castiglione, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Chiara Biella, Chiara Mercurio, Emanuela Pastorelli, Monica Lupi, Laura Paracchini, Laura Mannarino, Dietmar Krex, Federico Brandalise, Michele Mazzanti. TTFields reduce sensitivity in glioblastoma is associated with the functional expression of the chloride intracellular channel 1 and with voltage dependent sodium channel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1425.
Abstract 838: Development of cationic polypeptide-based adjuvants for cancer immunotherapy
Authors: DaeYong Lee, Kristin Huntoon, Wen Jiang, Betty Kim
Journal: Cancer Research (2023)

Abstract Stimulation of intracellular DNA sensors plays a crucial role in regulating innate immunity as well as bridging to adaptive immune responses. Although delivery of agonists can activate such innate immune sensors, their intracellular delivery are generally challenging due to vulnerability to enzymatic degradation, low water solubility, or electrostatic repulsions. To overcome the hurdles, we developed a synthetic cationic helical polypeptide that stimulated toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axes by triggering mitochondrial DNA release preferentially in APCs. We revealed that systemic administration of this polypeptide-based adjuvant generated pro-inflammatory responses in APCs, and subsequently primed cytotoxic T cells. Furthermore, the polypeptide treatment with immune checkpoint blockade (anti-programmed cell death protein 1: anti-PD1) synergistically improved tumor suppression and increase animal survival of breast tumor-bearing mice. Taken together, this study suggests that the multi-potent cationic polypeptide stimulated multiple innate immune sensors, thus providing a promising therapeutic strategy to generate meaningful anti-tumor effects. Citation Format: DaeYong Lee, Kristin Huntoon, Wen Jiang, Betty Kim. Development of cationic polypeptide-based adjuvants for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 838.
Abstract 3678: Rewiring of amino acid metabolism in neurofibromatosis type 1-related tumors
Authors: Martina La Spina
Journal: Cancer Research (2023)

Abstract Neurofibromatosis type 1 (NF1) is a tumor-predisposing genetic disorder caused by heterozygous mutations in the NF1 gene encoding for the tumor suppressor Neurofibromin. Biallelic NF1 inactivation in Schwann cells leads to the onset of neurofibromas, benign neoplasms that can cause severe medical complications and give rise to malignant peripheral nerve sheath tumors (MPNSTs), for which no treatment exists. Neurofibroma cells undergo bioenergetic changes required to sustain their malignant transformation. Our group has shown that inhibition of the mitochondrial chaperone TRAP1, a master metabolic regulator, hampers MPNST cell tumorigenicity. A growing number of evidence indicates that urea cycle (UC) dysregulation can redirect metabolic substrates to specific biosynthetic routes in many tumor cell types. We have found that a complete UC is absent in MPNST cell models, as they lack ornithine transcarbamylase (OTC), a key UC enzyme that converts ornithine into citrulline. In the absence of TRAP1, MPNST cells strongly reduce arginine levels and accumulate ornithine through the activity of the mitochondrial enzymes arginase 2 (ARG2) and ornithine aminotransferase (OAT). These changes can reverberate on glutamine and proline levels ultimately affecting extracellular matrix deposition, motility and ROS homeostasis, as well as on ornithine-dependent polyamine biosynthesis that can regulate cell growth and proliferation. Surprisingly, in the absence of TRAP1 MPNST cells also accumulate citrulline, even though they do not express either OTC or any nitric oxide synthase (NOS) isoform that converts arginine into citrulline. We ascribe citrulline production to the activity of dimethylarginine dimethylaminohydrolase (DDAH) enzymes, involved in the catabolism of asymmetric dimethylarginines. Induction of DDAHs indicates an elevated protein catabolism that could contribute to tune MPNST cell tumorigenicity. A thorough comprehension of the amino acid metabolism rewiring in NF1-related tumors may unveil new targetable liabilities of cancer cells to be exploited for the design of new effective therapeutic approaches. Citation Format: Martina La Spina. Rewiring of amino acid metabolism in neurofibromatosis type 1-related tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3678.
Abstract 3675: Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment
Authors: Yiling Chen, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong
Journal: Cancer Research (2023)

Abstract Ferroptosis is a novel immunogenic and regulated cell death caused by iron-dependent lipid peroxidation. Glutathione peroxidase 4(GPX4)/glutathione and ferroptosis suppressor protein 1(FSP1)/Coenzyme Q10(CoQ10) are two major anti-ferroptosis systems that prevent lipid ROS-induced cell death. Our current study unprecedentedly uncovered that the Mevalonate pathway (MVA) protects HCC from ferroptosis by two parallel mechanisms: 1) by providing the lipophilic antioxidant CoQ10 for FSP1; 2) by generating isopentenyl pyrophosphate (IPP), a substrate for Selenocysteine (Sec)-tRNA modification for selenoprotein GPX4 translation. Selenoproteins are a class of proteins composed of selenocysteine, the 21st amino acid not found in the codon table. Selenocysteine is recoded by the stop codon UGA and synthesized on its tRNA. The Sec-tRNA incorporates Sec into selenoproteins such as GPX4. We showed that perturbation of the MVA pathway by genetic knockdown or pharmacologic inhibition repressed CoQ10 synthesis and the translation of selenoproteins, thereby leading to lipid-derived ROS and ferroptotic cell death. Furthermore, we showed that Mevalonate diphosphate decarboxylase (MVD), a MVA enzyme, was a transcriptional target of Nuclear Factor Erythroid 2- related factor 2 (NRF2), a master regulator of oxidative stress response. High expression of MVD was associated with poor prognosis in HCC. Strikingly, MVD inhibitor treatment profoundly suppressed HCC. Reduced tumor size and increased tumor-infiltrated effector T cells and macrophages were found in vivo. To conclude, our study has provided novel mechanistic insight about how NRF2/MVA pathway promotes HCC and suggested that MVD might be a good prognostic indicator and therapeutic target in human HCC. Funding Support: RGC Postdoctoral Fellowship Scheme 2021/22 (Project #102010048) Citation Format: Yiling Chen, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong. Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3675.